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Elucidation of pathogenesis of influenza-related encephalopathy using functional failure in rat glia cells

利用大鼠胶质细胞功能衰竭阐明流感相关脑病的发病机制

基本信息

批准号：
14370249
负责人：
YOKOTA Shumpei
金额：
$ 7.62万
依托单位：
Yokohama City University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

项目摘要

The central nervous system (CNS) is an immune-privileged site by blood brain barrier (BBB). It is reported that glial cells such as microglia and astrocyte product cytokine in he CNS in normal and several disease states. Recent studies indicated that TNFa plays an important role in brain injury after various kind of insult (infection, ischemia, trauma). In this study, we established the experimental system of cytokine storm in the CNS by intracerabrospinal administration of lipopolysaccharide (LPS) and examined the effect of the proinflammatory cytokines in the CNS for brain and systemic. One hour after intracerabrospinal administration with LPS (30μg, 300μg), expression of IL-1^β, IL-6, TNFα mRNA was detected in rat brain by Rnase Protection Assay(RPA) and two hours after administration, cerebrospinal fluid(CSF) concentration of IL-1β, IL-6, TNFα increased. Histological examination proved activation of NFκB, apoptosis in rat brain, the description of blood brain barieer(BBB) by leak of FITC-Dextran(MW 10,000) from vessel in rat brain Serum concentration of IL-6, TNFα was increased by intracerebrospinal administration with high dose LPS. In conclusion, intracerebrospinal administration with LPS mediated activation of CNS immunosystem and production proinflammatory cytokine, such as IL-1β, IL-6, TNFα. Moreover, TNFα in the CNS mediated brain apoptosis and lead to BBB destruction. Finally peripheral cytokine concentration increased LPS and cytokine leaked through BBB.

中枢神经系统（CNS）是血脑屏障（BBB）的免疫特权部位。据报道，在正常和几种疾病状态下，中枢神经系统中的胶质细胞如小胶质细胞和星形胶质细胞产生细胞因子。近年来的研究表明，TNFa在各种损伤（感染、缺血、创伤）后的脑损伤中起重要作用。本研究通过脊髓内注射脂多糖（LPS）建立了中枢神经系统细胞因子风暴的实验系统，并研究了促炎细胞因子在中枢神经系统对脑和全身的影响。LPS （30μg、300μg）给药后1 h， Rnase Protection Assay（RPA）检测大鼠脑组织IL-1^β、IL-6、TNFα mRNA的表达；给药后2 h，脑脊液IL-1β、IL-6、TNFα浓度升高。组织学检查证实，大鼠脑内nf - κ b活化，大鼠脑内凋亡，大鼠脑血管中fitc -葡聚糖（mw10000）渗漏对血脑屏障（BBB）的描述，大鼠脑内高剂量LPS使血清IL-6、tnf - α浓度升高。综上所述，脑脊髓内注射LPS可激活CNS免疫系统并产生促炎细胞因子，如IL-1β、IL-6、tnf - α。此外，中枢神经系统中的TNFα介导脑细胞凋亡并导致血脑屏障破坏。末梢细胞因子浓度升高，脂多糖和细胞因子通过血脑屏障渗漏。